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Principal Investigator: Wen Jiang
Organization: UT SOUTHWESTERN MEDICAL CENTER
Fiscal Year: 2020
Award: $253,377
Funding agency: National Cancer Institute
Project Summary
Despite significant advances in the treatment of breast cancer, the metastatic form of the disease remains
highly lethal, with a 5-year overall survival rate of only around 20%. Even with the use of new, targeted
therapies such as antibodies against the human epidermal receptor 2 (HER2) expressed by cancer cells, over
70% of patients with metastatic diseases eventually become resistant to therapy. Advances in cancer
immunotherapy with immune checkpoint blockers have shown that harnessing the power of the body's immune
system can be an effective strategy to fight metastatic cancer. However, only a small proportion of patients
(~20%) respond to immune checkpoint blockers, and their effectiveness against breast cancer remains
uncertain. To overcome these challenges, we recently developed a multivalent bispecific nanobioconjugate
engager (mBiNE) that simultaneously engages HER2 receptor on breast cancer cells and pro-phagocytosis
molecules on macrophages to facilitate the clearance of HER2+ breast cancer by the immune system. The
current proposal explores the use of mBiNE to promote antitumor immune responses and to enhance the
effectiveness of immune checkpoint blockade against metastatic breast cancers. Aim 1 of the proposal will
examine whether mBiNE activates potent and broad antigen-specific antitumor immune responses against
HER2 overexpressing metastatic breast cancer. For Aim 2, we will elucidate the innate mechanisms within
macrophages by which mBiNE-induced tumor cell phagocytosis promotes the cross-priming of adaptive
antitumor immune responses. Finally, for Aim 3, we will investigate whether mBiNE can be safely combined
with anti-PD1 therapy to stimulate both the innate and adaptive immune responses against poorly
immunogenic metastatic breast cancer.
An extensive training and development program has been proposed under the guidance of a
multidisciplinary mentoring team consisting of physician-scientists, oncologists, immunologists, and tumor
biologists. My primary mentor, Dr. Yang-Xin Fu, is a physician scientist, and a recognized expert in innate
tumor immunity; my co-mentor, Dr. Wendy Woodward is known for her preclinical and clinical work with
aggressive types of breast cancers. They will be joined on my mentoring committee by Dr. Irving Weissman, a
pioneer in tumor immunology; Dr. Keith Knutson, a leader in breast cancer vaccine development; and Dr.
Patrick Hwu, an internationally recognized cancer immunotherapy expert, who will serve as an advisor. The
University of Texas Southwestern Medical Center provides an outstanding environment for my research and
career development. All of the resources and equipment critical to the proposed research are readily available
on campus, and I will have many opportunities to form collaborations with leaders in cancer immunotherapy.
Together, the proposed research, training and career development plan will ensure that I receive the best
mentorship available to become an independent investigator.
Terms: <55-kDa High-Affinity Calcium Binding Protein><Alferon><Antibodies><Antibody Therapy><Antigen-Presenting Cells><Antigens><Antitumor Response><Breast Cancer><Breast Cancer Cell><Breast Cancer Treatment><Breast Neoplasms><Breast Tumors><CAB-63><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Calcium-Binding Protein-3><Calregulin><Cancer Prognosis><Cancer Vaccine Related Development><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Clinical><Collaborations><Combination immunotherapy><Cross Presentation><Cross-Priming><Cyclic GMP><Detection><Development Plans><Development and Research><Disease><Disorder><Disseminated Malignant Neoplasm><EGF Receptor><EGFR><ERBB Protein><ERp60><Early treatment><Effectiveness><Endogenous Interferon Beta><Ensure><Environment><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Equipment><Fibroblast Interferon><Generations><Goals><Guanosine Cyclic Monophosphate><HACBP><HER1><Human><IFN><IFN Alpha><IFN-Beta><IFN-α><IFN-β><IFNa><IFNb><IFNα><Immune><Immune Cell Activation><Immune Targeting><Immune mediated therapy><Immune memory><Immune system><Immunes><Immunocompetent><Immunologic Memory><Immunological Memory><Immunologically Directed Therapy><Immunologist><Immunotherapy><Innate Immune Response><Interferon Alfa-n3><Interferon Type I><Interferon-alpha><Interferon-beta><Interferon-α><Interferon-β><Interferons><International><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Investigation><Investigators><Lead><Leukocyte Interferon><Lymphoblast Interferon><Lymphoblastoid Interferon><Malignant Cell><Mammary Cancer><Mammary Neoplasms><Mediating><Medical center><Mentors><Mentorship><Messenger RNA><Metastatic Cancer><Metastatic Malignant Neoplasm><Metastatic breast cancer><Mice><Mice Mammals><Modern Man><Molecular><Murine><Mus><Natural Interferon Beta><Natural human interferon beta><Nature><Normal Tissue><Normal tissue morphology><Oncologist><PD-1 antibody><PD-1 antibody therapy><PD-1 therapy><PD1 antibody><PD1 antibody therapy><PD1 based treatment><Pathway interactions><Patients><Pattern><Pb element><Peptides><Phagocytes><Phagocytic Cell><Phagocytosis><Phagosomes><Physicians><Production><Program Development><R & D><R&D><Receptor Protein><Receptor Signaling><Research><Research Personnel><Research Resources><Research Training><Researchers><Resistance><Resources><Scientist><Signal Transduction><Signal Transduction Systems><Signaling><Stimulator of Interferon Genes><Survival Rate><System><T cell response><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><TGF-alpha Receptor><TLR protein><Technology><Testing><Texas><Toll-Like Receptor Family Gene><Toll-like receptors><Toxic effect><Toxicities><Training><Transforming Growth Factor alpha Receptor><Tumor Antigens><Tumor Cell><Tumor Immunity><Tumor-Associated Antigen><Tumor-Derived><Universities><Urogastrone Receptor><Work><Yang><aPD-1><aPD-1 therapy><aPD-1 treatment><aPD1><aPD1 therapy><aPD1 treatment><accessory cell><adaptive immune response><advanced breast cancer><advanced stage breast cancer><allergic/immunologic body system><allergic/immunologic organ system><amebocyte><anamnestic reaction><anti programmed cell death 1><anti-PD-1><anti-PD-1 Ab><anti-PD-1 antibodies><anti-PD-1 monoclonal antibodies><anti-PD-1 therapy><anti-PD-1 treatment><anti-PD1><anti-PD1 Ab><anti-PD1 antibodies><anti-PD1 monoclonal antibodies><anti-PD1 therapy><anti-PD1 treatment><anti-cancer immunotherapy><anti-programmed cell death 1 therapy><anti-programmed cell death protein 1><anti-programmed cell death protein 1 antibodies><anti-programmed cell death protein 1 therapy><anti-tumor effect><anti-tumor immune response><anti-tumor immunity><anti-tumor response><antiPD-1><antiPD1><antibody based therapies><antibody treatment><antibody-based therapeutics><antibody-based treatment><anticancer immunotherapy><antitumor effect><antitumor immune response><antitumor immunity><biological signal transduction><breast cancer vaccine><breast tumor cell><c-erbB-1><c-erbB-1 Protein><cC1qR Protein><cGAMP STING><cGAMP-STING><cGAMP/STING><cGAS/STING><cGMP><calreticulin><cancer antigens><cancer cell><cancer immunity><cancer immunology><cancer immunotherapy><cancer vaccine development><career development><check point blockade><check point blocker><checkpoint blockade><checkpoint blockers><combinatorial immunotherapy><design><designing><dual immunotherapy><early therapy><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><fighting><heavy metal Pb><heavy metal lead><immune activation><immune check point blockade><immune check point blocker><immune checkpoint blockade><immune checkpoint blockers><immune competent><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunogenic><immunotherapy for cancer><immunotherapy of cancer><interventional strategy><mRNA><macrophage><malignant breast neoplasm><malignant breast tumor><mammary tumor><mouse model><multidisciplinary><murine model><nano medicinal><nano medicine><nanomedicinal><nanomedicine><neoplasm immunology><neoplastic cell><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><novel><novel therapeutic approach><novel therapeutic intervention><novel therapy approach><overexpress><overexpression><pathway><pre-clinical><preclinical><programmed cell death protein 1 therapy><proto-oncogene protein c-erbB-1><receptor><research and development><resistance to therapy><resistant><resistant to therapy><response><secondary immune response><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic resistance><therapy resistant><thymus derived lymphocyte><treatment resistance><tumor><tumor DNA><tumor cell DNA><tumor immunology><tumor-specific DNA><tumor-specific antigen><αPD-1><αPD1>